Role of Intracellular Calcium Stores and Calcium-Permeable AMPARs in Functional and Structural Plasticity in Mouse Hippocampal Slices

Memories are internal representations of life that can last in the order of minutes to years, and are largely experience-dependent. For example, the memory of an inconsequential event typically fades, unless they are closely related to a novel event, succinctly explained by the synaptic tag and capture (STC) hypothesis. The formation of short (STM)- or long - term memories (LTM) involve several biochemical changes that either increase or decrease synaptic efficacy. These changes are commonly referred to as Long-term potentiation (LTP) or depression (LTD). LTP can be differentiated into two forms based on their dependence (LTP2) or independence (LTP1) on protein synthesis (PS) and are hypothesized to be analogous to LTM and STM respectively. In both forms of LTP, calcium (Ca2+) signaling plays a vital role. However, Ca2+ has a number of different sources, the relative importance of which is poorly understood. Here I have investigated the role of calcium-permeable (CP)- AMPARs and Ca2+ release from intracellular stores. Using theta burst stimulation (TBS) of varied strength and patterning, I was able to selectively induce LTP1 (wTBS or cTBS) or a combination of LTP1 and 2 (sTBS). Combining these induction protocols with pharmacological agents, I have confirmed the role of CP-AMPARs and demonstrated that intracellular Ca2+ stores are required specifically for LTP2. To investigate STC, I delivered LTP 2 and LTP1 to independent inputs, which resulted in an enhancement of LTP1 due to STC. I confirmed the role of CP-AMPARs and demonstrated the importance of Ca2+ release from intracellular stores during the induction of LTP2 in STC. Furthermore, to address the question of the association between functional and structural plasticity under physiological conditions, I developed a method to monitor both simultaneously using field potential recordings and two-photon imaging, respectively. I found that functional plasticity induced by sTBS is associated with structural plasticity and that the structural plasticity is entirely dependent on the activation of CP-AMPARs. In conclusion, my findings provide novel insights to the synaptic basis of memory formation and highlight the importance of CP-AMPARs and calcium release from intracellular stores in this process.

Department dc:contributor.department

Physiology

Year dc:date.issued

2023

Author dc:creator

• Koek, Laura A

Advisor dc:contributor.advisor

• Collingridge, Graham L

• Calcium
• Calcium-permeable AMPA-receptor
• Long-term potentiation
• Protein synthesis-dependent plasticity
• Synaptic tag and capture
• Two-photon imaging

Statement dc:rights

• Attribution-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nd/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/127967

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/127967